Biomedical subjects

Anthony H Dickenson

Publications and source records attributed to Anthony H Dickenson.

At least 37 records · Page 2Linked to original sources

PubMed2004

Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain.

Nine voltage-gated sodium channels are expressed in complex patterns in mammalian nerve and muscle. Three channels, Na(v)1.7, Na(v)1.8, and Na(v)1.9, are expressed selectively in peripheral damage-sensing neurons. Because there are no selective blockers of these channels, we used gene ablation in mice to examine the function of Na(v)1.7 (PN1) in pain pathways. A global Na(v)1.7-null mutant was found to die shortly after birth. We therefore used the Cre-loxP system to generate nociceptor-specific knockouts. Na(v)1.8 is only expressed in peripheral, mainly nociceptive, sensory neurons. We knocked Cre recombinase into the Na(v)1.8 locus to generate heterozygous mice expressing Cre recombinase in Na(v)1.8-positive sensory neurons. Crossing these animals with mice where Na(v)1.7 exons 14 and 15 were flanked by loxP sites produced nociceptor-specific knockout mice that were viable and apparently normal. These animals showed increased mechanical and thermal pain thresholds. Remarkably, all inflammatory pain responses evoked by a range of stimuli, such as formalin, carrageenan, complete Freund's adjuvant, or nerve growth factor, were reduced or abolished. A congenital pain syndrome in humans recently has been mapped to the Na(v)1.7 gene, SCN9A. Dominant Na(v)1.7 mutations lead to edema, redness, warmth, and bilateral pain in human erythermalgia patients, confirming an important role for Na(v)1.7 in inflammatory pain. Nociceptor-specific gene ablation should prove useful in understanding the role of other broadly expressed genes in pain pathways.

Animals↗

PubMed2004

Descending serotonergic facilitation mediated through rat spinal 5HT3 receptors is unaltered following carrageenan inflammation.

A descending facilitatory drive originating from superficial dorsal horn NK1-expressing neurones and relaying through parabrachial and rostroventral medial medulla to act on deep dorsal horn neurones, mediated through spinal 5HT3 receptors, was recently documented. To determine if this pathway plays a role in the pathophysiology of inflammation, we investigated the effects of spinally administered ondansetron (a selective 5HT3 receptor antagonist) on deep dorsal horn neuronal responses in carrageenan inflamed and naïve animals using in vivo electrophysiology. The mechanical and thermal evoked responses of spinal neurones were dose dependently attenuated by ondansetron to a similar degree in both groups. In contrast, the electrically evoked responses (Abeta-, Adelta-, C-fibre evoked response and post-discharge) remained unaltered in both groups. Thus 5HT3 receptor mediated descending facilitation remains unaltered at this stage after tissue injury.

Animals↗

PubMed2004

Effects of spinally administered adenine on dorsal horn neuronal responses in a rat model of inflammation.

A novel G-protein-coupled receptor with adenine identified as the endogenous ligand has recently been described. In vivo electrophysiological techniques in the rat were used to record the response of dorsal horn neurones in response to transcutaneous electrical stimulation to the hindpaw receptive field. Spinal adenine (1-1000 microg) exerted facilitatory effects on the electrically-evoked neuronal responses, in a mildly dose-related manner. After establishment of carrageenan-induced inflammation to the hindpaw this excitatory effect of adenine was still apparent, yet reduced. C-fibre-evoked responses and other nociceptive related measures were most susceptible to the effects of adenine, whereas non-nociceptive Abeta-fibre evoked activity remained unaffected. Thus, activation of the adenine receptor site, via spinally applied adenine, suggests a pronociceptive role in nociceptive sensory transmission.

Adenine↗

PubMed2004

Nerve injury alters the effects of interleukin-6 on nociceptive transmission in peripheral afferents.

Interleukin-6 (IL-6) is markedly upregulated in the peripheral and central nervous systems following nerve injury; however, the functional effects of this are unclear. This study investigates the effect of peripheral interleukin-6 on nociceptive transmission in naive and neuropathic states. Using an in vitro rat skin-nerve preparation, 50 ng interleukin-6 inhibited responses of single nociceptive fibers to noxious heat. A 20-ng sample of interleukin-6 only inhibited heat responses in the presence of soluble interleukin-6 receptors. To examine in vivo effects of peripheral interleukin-6, extracellular recordings from dorsal horn neurons were made in anaesthetised naive, sham-operated and neuropathic (spinal nerve ligated) rats. Peripheral interleukin-6 (40-100 ng) markedly inhibited all naturally evoked neuronal responses in naive rats, yet only neuronal responses to heat in neuropathic rats. Behaviourally, intraplantar administration of interleukin-6 (0.01-1 microg) elicited ipsilateral thermal hypoalgesia in naive rats. Thus, interleukin-6 inhibits normal peripheral nociceptive transmission, yet such anti-nociceptive effects are attenuated following nerve injury in a modality-specific manner.

Action Potentials↗

PubMed2004

Cholecystokinin fails to block the spinal inhibitory effects of nociceptin in sham operated and neuropathic rats.

Cholecystokinin (CCK) has a number of roles in the central nervous system and can reduce the analgesic effect of activation of mu (micro), delta (delta) and kappa (kappa) opioid receptors. CCK has been proposed to be a major reason for reduced effects of morphine after nerve injury. This study examines if CCK modulates the effect of the Opioid Receptor Like-1 (ORL1) agonist, nociceptin on dorsal horn neurone activity in vivo in the spinal nerve ligation model of neuropathic pain compared with sham-operated and naive rats. In naive and neuropathic rats nociceptin alone inhibited the C-fibre evoked response, post-discharge, wind-up and input, while in sham operated rats nociceptin did not cause any inhibition but by contrast caused a facilitation of post-discharge and wind-up. CCK alone had no significant effect, although did cause slight facilitation in the three groups. In the presence of CCK the inhibitory effect of nocieceptin was blocked in naive animals, but in contrast the inhibitory effect of nociceptin was enhanced by CCK in sham and neuropathic rats. These results emphasize the differences between ORL1 and other opioid receptors. This loss of the inhibitory effect of CCK on nociceptin after nerve injury may be of clinical interest in the treatment of neuropathic pain.

Animals↗

PubMed2004

In vivo electrophysiology of dorsal-horn neurons.

The dorsal horn of the spinal cord is a key relay in the transmission of sensory information to the brain. Furthermore, this circuitry of spinal-cord neurons, and hence the spinal processing of sensory information, is subject to a great deal of plasticity, both pharmacological and physiological, in persistent pain states. This chapter describes in detail the procedure by which the activity and pharmacological modulation of these dorsal-horn neurons can be recorded in vivo in anesthetized rats, allowing a comprehensive study of spinal sensory processing in an intact and integrated system. The chapter covers the surgical preparation of the animal for electrophysiological recording; isolating and recording the activity of a single dorsal-horn neuron; and identifying the type of dorsal-horn neuron recorded by characterizing the neuronal response to a variety of peripheral stimuli. The study of these neuronal responses in a variety of persistent pain states, such as carrageenan-induced inflammation and neuropathy induced by L5/L6 spinal nerve ligation, together with the study of their pharmacological modulation by locally or systemically administered drugs, is also described.

Action Potentials↗

PubMed2004

Electrophysiological characterisations of rat lamina I dorsal horn neurones and the involvement of excitatory amino acid receptors.

Lamina I of the spinal cord plays a key role in sensory transmission between afferent activity and the CNS. Studies have shown lamina I neurones to have distinct response properties compared to deep dorsal horn neurones, but little is known regarding excitatory amino acid mechanisms in their responses. Spinal electrophysiological recordings of lamina I neurones confirmed that the majority of these neurones (74%) are nociceptive specific (NS) in their responses, of which 18% can be termed polymodal nociceptive (HPC) (13% of the total population). The remainder (26%) were wide dynamic range. Lamina I neurones had smaller mechanical and heat-evoked responses compared to deeper dorsal horn neurones. The electrically evoked responses were also smaller, with a distinct lack of an NMDA-mediated 'wind-up' effect. NBQX (AMPA receptor antagonist, 0.5, 5, 50 microg/50 microl) produced dose-dependent inhibitions of the electrically evoked neuronal responses, but APV (NMDA receptor antagonist, 50, 100, 500 microg/50 microl) had minimal effects on their responses. These results implicate mainly AMPA receptors in the responses of lamina I neurones. Bicuculline (GABA(A) receptor antagonist, 0.5, 5, 50 microg/50 microl) demonstrated a role exerted by GABA(A) receptors in the control of A-delta fibre-mediated mechanical responses in lamina I. Overall, this study describes a high threshold, AMPA receptor possessing population of lamina I neurones, which seem to lack functional NMDA receptors, and are partially controlled by GABA(A) receptor activity.

2-Amino-5-phosphonovalerate↗

PubMed2004

Bad news from the brain: descending 5-HT pathways that control spinal pain processing.

The identification of opioid systems led to much of the early work on pain pharmacology being based on understanding inhibitory mechanisms of analgesia. However, hyperalgesia and allodynia are common clinical symptoms and therefore hyperexcitability must be a major component of pain. Thus, the emphasis of current research into pain has shifted to understanding excitatory pathways that underlie neuronal sensitization and potentiation. Although much evidence supports the presence of descending inhibitory mechanisms of pain, reports of facilitatory pathways from the brainstem have been scarce. In this article, we review evidence for facilitatory 5-HT pathways that link spinal cord and brainstem areas involved in mood and emotions. Because pain encompasses affective aspects, we suggest that these 5-HT pathways and other circuits are important in determining the levels of pain, the outcome of drug treatments and provide a mechanism whereby emotions can alter pain perception.

Animals↗

PubMed2003

Spinal interleukin-6 (IL-6) inhibits nociceptive transmission following neuropathy.

Interleukin-6 (IL-6) is a neuropoietic cytokine which is dramatically upregulated following peripheral nerve injury at the site of injury, in the dorsal root ganglion (DRG) and in the spinal cord. The functional effects of IL-6 in nociception in normal conditions and following nerve injury are unclear. Thus the aim of this study was to assess the effect of spinal IL-6 administration on nociceptive transmission in naive, sham-operated and neuropathic (spinal nerve ligation, SNL) rats using in vivo electrophysiology to elucidate the possible role of IL-6 in neuropathic pain. In anaesthetised rats, extracellular recordings were made from individual convergent dorsal horn neurones following electrical and natural (mechanical and thermal) stimulation of peripheral receptive fields. Exogenous spinal IL-6 (100-500 ng) had no significant effect on electrically evoked neuronal responses in naive rats. In contrast, following neuropathy, spinal IL-6 produced a dose-related inhibition of the electrically evoked C-fibre, initial C-fibre and measures of neuronal hyperexcitability (post discharge and wind-up). In addition, spinal IL-6 markedly inhibited mechanical neuronal responses in neuropathic rats. Higher doses of spinal IL-6 also inhibited, to a lesser degree, the initial C-fibre, post discharge and wind-up responses in sham-operated rats. These studies show that following nerve injury the actions of the cytokine alter so that spinal administration of IL-6 elicits anti-nociceptive effects not observed under normal conditions. Moreover, the inhibitory effects of IL-6 on C-fibre activity and neuronal hyperexcitability, suggest IL-6 to be a potential modulator of neuropathic pain.

Animals↗

PubMed2003

KCNQ/M currents in sensory neurons: significance for pain therapy.

Neuronal hyperexcitability is a feature of epilepsy and both inflammatory and neuropathic pain. M currents [IK(M)] play a key role in regulating neuronal excitability, and mutations in neuronal KCNQ2/3 subunits, the molecular correlates of IK(M), have previously been linked to benign familial neonatal epilepsy. Here, we demonstrate that KCNQ/M channels are also present in nociceptive sensory systems. IK(M) was identified, on the basis of biophysical and pharmacological properties, in cultured neurons isolated from dorsal root ganglia (DRGs) from 17-d-old rats. Currents were inhibited by the M-channel blockers linopirdine (IC50, 2.1 microm) and XE991 (IC50, 0.26 microm) and enhanced by retigabine (10 microm). The expression of neuronal KCNQ subunits in DRG neurons was confirmed using reverse transcription-PCR and single-cell PCR analysis and by immunofluorescence. Retigabine, applied to the dorsal spinal cord, inhibited C and Adelta fiber-mediated responses of dorsal horn neurons evoked by natural or electrical afferent stimulation and the progressive "windup" discharge with repetitive stimulation in normal rats and in rats subjected to spinal nerve ligation. Retigabine also inhibited responses to intrapaw application of carrageenan in a rat model of chronic pain; this was reversed by XE991. It is suggested that IK(M) plays a key role in controlling the excitability of nociceptors and may represent a novel analgesic target.

Animals↗

PubMed2003

Effects of GCP-II inhibition on responses of dorsal horn neurones after inflammation and neuropathy: an electrophysiological study in the rat.

N-Acetylaspartylglutamate (NAAG) is a peptide neurotransmitter present in the brain and spinal cord. It is hydrolysed by glutamate carboxypeptidase II (GCPII); thus, the GCP-II inhibitor 2-[phosphono-methyl]-pentanedioic acid (2-PMPA) protects endogenous NAAG from degradation, allowing its effects to be studied in vivo. We recorded the effect of spinal 2-PMPA (50-1000 microg) on the electrical-evoked activity of dorsal horn neurones in normal and carrageenan-inflamed animals, and in the spinal nerve ligation (SNL) model of neuropathy and sham-operated animals. In normal animals, 1000 microg 2-PMPA selectively inhibited noxious-evoked activity (input, post-discharge and C- and Adelta-fibre-evoked responses), and not low threshold Abeta-fibre-evoked responses. After carrageenan inflammation, the lower dose of 100 microg 2-PMPA inhibited input, post-discharge, C- and Adelta-fibre-evoked responses by a significantly greater amount than the same dose in normal animals. 2-PMPA inhibited neuronal responses less consistently in sham-operated and SNL animals, and effects were not significantly different from those seen in normal animals. NAAG is an agonist at the inhibitory metabotropic glutamate receptor mGluR3, and 2-PMPA may inhibit nociceptive transmission in normal animals by elevating synaptic NAAG levels, allowing it to activate mGluR3 and thus reducing transmitter release from afferent nerve terminals. mGluR3 expression in the superficial dorsal horn is upregulated after peripheral inflammation, perhaps explaining the greater inhibition of neuronal responses we observed after carrageenan inflammation. These results support an important role of endogenous NAAG in the spinal processing of noxious information.

Animals↗

PubMed2003

The coding of noxious mechanical and thermal stimuli of deep dorsal horn neurones is attenuated in NK1 knockout mice.

Previous behavioural evidence has shown that NK1 receptor gene knockout (NK1 -/-) mice display altered nociceptive responses following tissue or peripheral nerve injury. A single electrophysiological study reported an attenuation of wind-up and responses to mustard oil application. Although the behavioural results implicate SP and its receptor (NK1-R) in the transmission of noxious high intensity pain, little is known regarding the spinal neuronal substrates and the modalities involved. We have addressed this using in vivo electrophysiology and recordings of deep dorsal horn neurones in urethane-anaesthetised C57B6 x 129/sv mice to reveal a marked deficit in mechanical and thermal coding, selectively encompassing the suprathreshold range of noxious stimuli. The frequency-dependent increase in neuronal activity following repetitive C-fibre stimulation (wind-up) was also abolished in spinal neurones of NK1-R knockout mice. Quantification of the receptive field size of spinal neurones, mapped with low- and high-intensity mechanical punctate stimuli, revealed no differences between NK1 -/- and wildtype mice. We conclude that NK1-Rs are important in the high intensity noxious signalling of acute peripheral (mechanical/thermal) stimuli and this may result from the lack of wind-up and/or the disruption of spinal-bulbo-spinal loops.

Action Potentials↗

PubMed2003

Does a single intravenous injection of the 5HT3 receptor antagonist ondansetron have an analgesic effect in neuropathic pain? A double-blinded, placebo-controlled cross-over study.

UNLABELLED: Neurokinin-1-expressing neurones in lamina I to III of the spinal cord are intimately involved in the regulation of ascending and spino-bulbal pathways that regulate excitatory transmission. In experimental animals, ablation of these neurones reduces the responses to a variety of nociceptive stimuli. Furthermore, in animals, spinal application of the selective 5HT3 receptor antagonist ondansetron mimics these effects, indicating that 5HT3 receptors play a pronociceptive role and mediate descending excitatory controls that allow spinal neurones to fully code peripheral stimuli. In this study, we examined the potential analgesic effect of a single IV injection of ondansetron in humans with chronic neuropathic pain. Each consenting subject received a single IV injection of 8 mg ondansetron and placebo in varying order at least 1 wk apart with pain scores being recorded for the 48 h preceding and after each injection. Pain scores were significantly reduced 2 h after ondansetron injection (but at no other time point). This suggests that ondansetron can have an analgesic effect in neuropathic pain. Side effects were minor and infrequent. IMPLICATIONS: The selective 5HT3 receptor antagonist ondansetron, currently used as an antiemetic, may also have analgesic properties. Side effects with a single IV injection are infrequent and usually mild.

Adult↗

PubMed2002

Neuropharmacologic targets and agents in fibromyalgia.

Chronic widespread pain is a primary feature of fibromyalgia and is a symptom that is poorly managed in many patients. In addition, patients often experience fatigue, sleep disturbances, and anxiety. Its etiology is largely unknown. The successful clinical management of this syndrome relies on a multidisciplinary approach, employing pharmacologic and nonpharmacologic treatments. Clinical evidence on the symptoms and characteristics of fibromyalgia suggests a central mechanism behind the pathogenesis of this syndrome. It is likely that drugs with central actions will prove to be effective against a number of symptoms. This article aims to outline some of the potential spinal pharmacologic targets that may be used to treat this condition.

Central Nervous System Agents↗

PubMed2002

Nerve injury induces plasticity that results in spinal inhibitory effects of galanin.

Galanin is a 29-amino-acid neuropeptide that has been implicated in the processes of nociception. This study examines the effect of exogenous galanin on dorsal horn neurone activity in vivo in the spinal nerve ligation (SNL) model of neuropathic pain. SNL rats but not naive or sham-operated rats exhibited behaviour indicative of allodynia. In anaesthetized rats, extracellular recordings were made from individual convergent dorsal horn neurones following stimulation of peripheral receptive fields electrically or with natural (innocuous mechanical, noxious mechanical and noxious thermal) stimuli. Spinal administration of galanin (0.5-50 microg) caused a slight facilitation of the neuronal responses to natural and electrical stimuli in naive rats and up to a 65% inhibition of neuronal responses in sham-operated rats following 50 microg galanin. In contrast, there was a marked inhibition of up to 80% of responses to both natural and electrical stimuli in SNL rats following spinal galanin administration. These results suggest that following peripheral nerve injury, there is plasticity in the levels of galanin and/or its receptors at spinal cord level so that the effect of exogenous galanin favours inhibitory function.

Animals↗

PubMed2002

Superficial NK1-expressing neurons control spinal excitability through activation of descending pathways.

The increase in pain sensitivity that follows injury is regulated by superficially located projection neurons in the dorsal horn of the spinal cord that express the neurokinin-1 (NK1) receptor. After selective ablation of these neurons in rats, we identified changes in receptive field size, mechanical and thermal coding and central sensitization of deeper dorsal horn neurons that are important for both pain sensations and reflexes. We were able to reproduce these changes by pharmacological block of descending serotonergic facilitatory pathways. Using Fos histochemistry, we found changes in the activation of serotonergic neurons in the brainstem as well as evidence for a loss of descending control of spinal excitability. We conclude that NK1-positive spinal projection neurons, activated by primary afferent input, project to higher brain areas that control spinal excitability--and therefore pain sensitivity--primarily through descending pathways from the brainstem.

Animals↗

PubMed2002

Neurobiology of neuropathic pain: mode of action of anticonvulsants.

Anticonvulsants are widely used for the treatment of neuropathic pain. Here we review the evidence for a number of peripheral and central changes after nerve injury that may provide a basis for the mechanisms of action of anticonvulsant therapies. The roles of sodium channels, calcium channels, and central glutamate mechanisms are emphasized as the main targets for anticonvulsant drugs in neuropathic pain states. The focus of this article is on anticonvulsants; however, opioids and antidepressants can also be effective in increasing inhibitions to control of pain in a manner similar to that of the enhancement of gamma-aminobutyric acid (GABA) function by antiepileptic drugs. A brief account of these approaches to neuropathic pain is also given.

Analgesics↗

PubMed2002

Electrophysiologic characterization of the antinociceptive actions of S18616, a novel and potent alpha 2-adrenoceptor agonist, after acute and persistent pain states.

alpha (2)-Adrenoceptor (AR) agonists are active in behavioral models of persistent pain involving tissue and nerve damage. We evaluated the spinal effect of a novel, potent, and selective alpha (2)-AR agonist, [7,8](2-chlorobenzo)-2-amino-1-aza-3-oxa[4,5]spirodeca-1,7-diene (S18616), on the responses of dorsal horn neurons in halothane-anesthetized rats. Intrathecal administration of S18616 (0.1 to 3.0 microg) dose-dependently suppressed C- and A delta-fiber evoked responses but not the A beta-fiber evoked response. Drug effects were reversed by the alpha (2)-AR antagonists, atipamezole and idazoxan (100 microg). In rats with unilateral spinal nerve (L5-L6) ligation performed 2 weeks before study, S18616 (0.1 to 3.0 microg) dose-dependently suppressed the C- and A delta-fiber evoked responses and blocked "wind-up" in these neurons. The potency was comparable between nerve-injured and sham-operated rats, and S18616 was equally effective against responses to thermal and high-intensity mechanical stimuli. Interestingly, the effectiveness of S18616 on the low-intensity mechanical evoked response was significantly enhanced after nerve injury. Finally, S18616 (0.3 and 3.0 microg) reduced the neuronal responses produced by intraplantar injection of formalin. In conclusion, S18616 dose-dependently and potently inhibits the responses of dorsal horn neurons to peripheral stimulation in normal, inflamed, and neuropathic rats. These data support the use of spinal S18616 and other alpha (2)-AR agonists in the management of clinical pain.

Journal Article↗